Physiological cooling agents (or coolants) are constantly gaining ground in various consumer applications due to their ability of improving desirable sensate properties of the products. The desired sensate properties are generally explained by the chemical action of such compounds on the nerve endings responsible for the sensation of cold. Common applications and uses for these compounds include, but are not limited to foods, beverages, flavors, pharmaceuticals, perfumes, and miscellaneous cosmetic goods.
One of the most well-known physiological coolants is l-menthol, a compound having the structure (1) shown below, and which has been used in several of the above mentioned applications for a very long time. In particular, l-menthol has an excellent cooling strength, low sensitivity threshold, and relatively low price.
However, menthol also exhibits some undesirable properties, such as a strong “stinging” smell, a somewhat bitter taste, and it has relatively high volatility. These disadvantages of l-menthol have somewhat limited its utility in various applications and therefore stimulated an intense search for suitable physiological cooling agents that possess a low volatility and exhibit a relatively weak odor or even no odor at all.
The primary direction of physiological coolant compound research has focused toward the synthesis of molecules having a similar hydrocarbon skeleton as menthol, but which also comprise a much “heavier” functional group instead of the hydroxyl functional group. As a result, a number of synthetic menthol substitutes have been developed and commercialized. These substitutes include Menthyl Lactate (2), Menthyloxy Propane Diol (commonly referred to as “MPD”) (3), Monomenthyl Succinate (4), and N-ethyl-p-menthane-3-carboxamide (commonly referred to as WS-3) (5).

WS-3 is widely considered to be the strongest of coolants 2 through 5 illustrated above and is representative of a larger group of N-monosubstituted p-menthane-3-carboxamides of the general structure 6 set forth below and which also potentially provide desirable coolant properties.

With specific reference to structure 6, substituent “X” is commonly selected from the lower linear or branched alkyl substituents, functionally substituted alkyl substituents, or aryl substituents. To that end, U.S. Pat. Nos. 4,060,091; 4,136,163; 4,150,052; 4,178,459; 4,193,936; and 4,226,988, the entire disclosures of which are hereby incorporated by reference for all purposes, give a comparison of cooling strengths of certain N-monosubstituted p-menthane-3-carboxamides numerically expressed as sensitivity thresholds in μg, wherein a lower threshold value correlates to a stronger coolant effect. Of the compared compounds, the only commercially used N-monosubstituted p-menthane-3-carboxamide compound is the WS-3 coolant, having a sensitivity threshold of 0.3 μg.
According to the above mentioned patent references, some N-monosubstituted p-menthane-3-carboxamides of general structure 6 above have proven to be stronger coolants than WS-3. For example compound 7, wherein X represents an m,p-dimethylphenyl substituent, has a sensitivity threshold of 0.1 μg; compound 8, wherein X represents an m-hydroxy-p-methylphenyl-substituent, has a sensitivity threshold of 0.1 μg; compound 9, wherein X represents a p-methoxyphenyl-substituent, has a sensitivity threshold of 0.1 μg, and a glycine derivative of structure 10, wherein X represents —CH2COOC2H5, has a sensitivity threshold of 0.2 μg. Thus, compound 10 is 1.5 times stronger than WS-3 (compound 5).

The absence of commercial interest in the compounds 7, 8 and 9 is recognized due to the toxicology considerations implicated by the presence of the benzene ring. However, it has been unclear why the glycine derivative 10 has not attracted commercial interest, especially in view of an article containing additional corrected data on the strength of p-menthane-3-carboxamide coolants, which reported that glycine derivative 10 actually had a sensitivity threshold of 0.13 μg, which is approximately 1.5 times stronger than compound 5, which actually had a 0.2 μg threshold (J. Soc. Cosmet. Chem., 1978, vol. 29, pp. 185–200). To that end, the answer can be found in German reference DE 2,503,555, which teaches that compound 10 actually imparts a more bitter taste to a flavor composition when compared to a control.
Therefore, there is still a need in the art for a suitable physiological cooling agent possessing a high cooling activity.